Neuroimaging techniques are used to study the effect of antiepileptic drugs on cerebral glucose metabolism. In our most recent investigations, we found that valproic acid reduced cerebral blood flow (CBF) and glucose metabolism to the same degree as phenytoin (PHT) or carbamazepine (CBZ) but less than phenobarbital. The effect was most prominent in the thalamus, which may be related to the efficacy of valproic acid against absence seizures. Endogenous opiates have been implicated in the pathophysiology of epilepsy. 18F cyclofoxy, a naltrexone analogue, was used to image mu and kappa opiate receptors in patients with complex partial seizures. We found, in a few of the patients, increased opiate ligand binding ipsilateral to the epileptic focus, but no difference in the group as a whole. In the rat kainic acid model of epilepsy, bilateral decreases in dentate gyrus dynorphin immunohistochemical staining occurred despite unilateral cell loss on Nissel staining. No changes in met~enkephalin were found, supporting the hypothesis that kappa but not delta receptors are down~regulated. We have evaluated the effect of drug withdrawal on seizure frequency in order to assess the presence or absence of transient exacerbations which could be distingushed from a simple loss of drug effect. This was clearly present in the case of phenobarbital and CBZ, but absent for PHT. For CBZ, rate of discontinuation was significantly related to seizure frequency. Neuropsychiatric disorders such as panic were increased during drug withdrawal. These data are important for clinical practice. A physician wishing to withdraw a drug known to cause a transient exacerbation during taper may be more likely to perservere when seizures increase. We have conducted two double~blind placebo controlled trials of felbamate, an experimental anti~epileptic drug, in patients with complex partial seizures and the Lennox~Gastaut syndrome, a severe childhood epileptic encephalopathy. Patients are entered into the complex partial seizure trial after they have been tapered off their other drugs for surgical monitoring. This process simplifies data collection and clinical screening for several potential trials.